.alpha.-L-aspartyl-L-phenylalanine methyl ester (hereinafter abbreviated as .alpha.-APM) is a useful substance as an artificial dipeptide sweetening agent. It has a sweetness approximately 200 times that of cane sugar as well as a similar sweet taste to cane sugar and is of low calory so that it is in ever-increasing demand as a diet sweetening agent.
Numerous preparation processes of .alpha.-APM have so far been disclosed. There may be cited a variety of processes, for example, (1) a process which comprises condensating the hydrochloride of aspartic acid anhydride with L-phenylalanine methyl ester (Japanese Patent Publication No. 40069/1976), (2) a process which comprises condensating N-protective aspartic acid anhydride with L-phenylalanine methyl ester followed by deprotection (Japanese Patent Laid-Open Nos. 1370/1971 and 113841/1976), (3) a process which comprises reacting N-protective aspartic acid-62 -benzyl ester with L-phenylalanine methyl ester in the presence of a condensating agent followed by de-protection (Japanese Patent Laid-Open No. 130846/1984) and (4) a process which comprises reacting N-carboxyaspartic acid anhydride with L-phenylalanine methyl ester (Japanese Patent Laid-Open No. 96557/1973).
However, all of these processes employ L-phenylalanine methyl ester as one of the raw materials, requiring complex steps of methyl-esterification of L-phenylalanine. Moreover, according to the investigations of the present inventors, it has been found that L-phenylalanine methyl ester is such a compound that its free two molecules are liable to condensate and cyclize to 2,5-dibenzyl-3,6-dioxo-piperazine in a solution and thus has problems in its stability. This fact is responsible for the various troubles occurring in its industrial production.
Accordingly, it is desirable to develop a process which is free of these disadvantages in the production of .alpha.-APM, i.e., a process in which other raw materials than L-phenylalanine methyl ester are used.
As a process for preparing .alpha.-APM which uses other raw materials than L-phenylalanine methyl ester, there have been disclosed a process for preparing .alpha.-APM which comprises condensating N-formyl aspartic acid anhydride with L-phenylalanine in glacial acetic acid to form N-formyl-.alpha.-L-aspartyl-L-phenylalanine, de-formylating the N-formyl-.alpha.-L-aspartyl-L-phenylalanine to form .alpha.-L-aspartyl-L-phenylalanine, and esterifying said compound in methanol (Japanese Patent Publication No. 26133/1980), and a process in which the esterification step of .alpha.-L-aspartyl-L-phenylalanine to .alpha.-APM in the above process is improved (Japanese Patent Laid-Open No. 82752/1978).
However, since the former process brings about the esterification reaction in a substantially non-aqueous solution, the reaction has practically no freedom of selectivity so that not only the intended esterification but also the esterification of the .beta.-carboxyl group of aspartic acid as well as the diesterification takes place to a large extent. Therefore, the process suffers such disadvantages as low yields of .alpha.-APM.
The latter process brings about the esterification in the presence of water so as to increase the selectivity toward .alpha.-APM. However, the yield of isolation of .alpha.-APM is at most 50-60% based on .alpha.-L-aspartyl-L-phenylalanine and thus is insufficient.
As another process in which L-phenylalanine methyl ester is not used, there has recently been disclosed a process for preparing .alpha.-APM which comprises condensating the N-carboxylic acid anhydride of L-aspartic acid-.beta.-methyl ester with L-phenylalanine to produce .alpha.-L-aspartyl L-phenylalanine-.beta. -methyl ester and subjecting said compound to intramolecular transesterification in an aqueous hydrochloric acid solution containing methanol (Japanese Patent Laid-Open Nos. 225152/1984 and 225153/1984).
However, in this process, the esterification for producing the .beta.-methyl ester of aspartic acid is poor in selectivity and thus is low in yield. Further, the N-carboxylic acid anhydride of aspartic acid-.beta.-methyl ester, which is produced by reacting aspartic acid-.beta.-methyl ester with phosgene, is liable to polymerize by being brought into contact with a base or other causes. Therefore, this process is disadvantageous from the industrial viewpoint.
As has been described above, the conventional preparation processes of .alpha.-APM have demerits in the stability of its intermediates, in yield or in safety. Thus, it is the existing state of art that there are no efficient processes for preparing .alpha.-APM.